WGS of MTBC strains from Namibia

Background. Namibia is among the thirty high burden tuberculosis (TB) countries with an estimated incidence of 460 per 100,000 population and around 800 new multidrug resistant (MDR) TB cases per year. Still, data on transmission and evolution of drug-resistant Mycobacterium tuberculosis complex (Mtbc) strains are not available. Methods. Whole genome sequencing data of a convenient sample of 136 rifampicin resistant (RIFr) Mtbc strains obtained in 2016, 2017, and 2018 were used for a phylogenetic classification, resistance prediction and cluster analysis (12 single nucleotide polymorphism threshold) and linked with classical phenotypic drug susceptibility (pDST) data. Results. High first line drug resistance rates were detected with roughly 50 % of the strains investigated being resistant against all first line drugs. Furthermore, 13 % of the MDR Mtbc strains were already pre-extensively drug resistant (XDR). The cluster rate was high with 74.6 % among MDR, and 85 % among pre-XDR strains and clusters ranging in size from two to 25 isolates (cl22). A significant proportion of strains had borderline low-level resistance mutations e.g., inhA promotor mutations or rpoB L430P. Accordingly, 25 % of the RIFr strains tested susceptible by pDST. Finally, we determined a potentially new bedaquiline resistance mutation (Rv0678 D88G) occurring in two independent clusters. Conclusions. High first line resistance rates in line with emerging pre-XDR and likely bedaquiline resistance linked with ongoing recent transmission of MDR Mtbc clones underline the urgent need for the implementation of interventions that allow rapid diagnostics to break MDR-TB transmission chains in the country. A borderline RIFr mutation in the dominant outbreak strain causing discrepancies between phenotypic and genotypic resistance testing may require breakpoint adjustments, but also allow individualized regimens with high dose treatment.